High-throughput mapping of antigen specificity to B-cell-receptor sequence for characterizing antibody responses in HIV-vaccinated and infected individuals
B 细胞受体序列抗原特异性的高通量图谱,用于表征 HIV 疫苗接种者和感染者的抗体反应
基本信息
- 批准号:10478203
- 负责人:
- 金额:$ 85.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-02 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAntibodiesAntibody RepertoireAntibody ResponseAntibody TherapyAntigen TargetingAntigensAtlasesB-Cell Antigen ReceptorB-Lymphocyte EpitopesB-LymphocytesBar CodesBenchmarkingBinding SitesBiological AssayCell LineCellsCharacteristicsCollectionComplexDNAEpitope MappingEpitopesEventGenerationsGoalsHIVHIV InfectionsHIV Vaccine Trials NetworkHIV-1HIV-1 vaccineHumanImmune systemImmunodominant EpitopesIndividualInfectionKnock-outLeadLibrariesLightLinkMapsMeasuresMonoclonal AntibodiesMutationPeptidesPerformancePolysaccharidesPreventionProcessRecoveryResolutionSamplingSequence DeterminationSpecificityTechnologyTimeVaccinatedVaccinationVaccine DesignVaccinesValidationanalysis pipelineantigen bindingcell determinationco-infectioncohortexperimental studynext generation sequencingnovelpathogenpreventresponsescreeningtechnology developmenttoolvaccine candidatevaccine-induced antibodies
项目摘要
Project Summary. The search for an effective HIV-1 vaccine remains a top priority, and a deeper
understanding of how the immune system recognizes HIV-1 can help inform vaccine design. Lately, much
effort has focused on understanding antibody responses to HIV-1 infection and vaccination, since antibodies
have proven useful in therapy and prevention, and as templates for antibody-specific vaccine design. While
antibody responses to HIV-1 are polyclonal and complex, advances in next-generation sequencing (NGS)
technologies enable us to see such polyclonal responses at an unprecedented resolution, as a collection of
individual monoclonal antibody sequences. Sequence identification is typically followed by functional antibody
characterization, a primary component of which is the mapping of antigen/epitope specificity.
A major challenge with the standard antibody analysis pipeline is that the sequence identification and
functional characterization processes for antibodies are generally decoupled. This prevents truly high-
throughput mapping of antibody-antigen specificity, providing only limited information for a small subset of
selected antibody sequences from any given sample. To address this challenge, here we propose to develop a
technology that, for a given sample, will enable the mapping of antibody sequence to antigen specificity from a
single high-throughput experiment. The technology, LIBRA-seq (LInking B-cell Receptor to Antigen specificity
through sequencing), involves physically mixing a B-cell sample with a (theoretically unlimited) pool of
barcoded antigens, thus enabling the simultaneous recovery of: (i) paired heavy-light chain BCR sequences
and (ii) antigen specificity for a given B cell. In particular, this technology development project will broadly focus
on two specific aims: In Specific Aim 1, we will evaluate the effect of different antigen barcoding strategies and
other assay variables on LIBRA-seq accuracy and performance. The goal in this aim is to optimize the LIBRA-
seq ability to accurately detect BCR sequence and antigen specificity from a sequencing experiment. In
Specific Aim 2, we will aim to simultaneously map the target epitope of a given HIV-specific B cell, by
screening a cocktail of antigens with epitope-knockout mutations along with the wildtype antigens. These
efforts will not only lead to the identification of HIV-specific B cells, but will also provide residue-level
information about the specific epitope target on the antigen from the same high-throughput experiment.
Ultimately, for a given infection or vaccination sample, the LIBRA-seq technology will provide the ability
to recover antibody sequence and antigen specificity for tens to hundreds of thousands of B cells at the single-
cell level. To demonstrate the utility of LIBRA-seq, we will characterize samples from HIV-1 infection and
vaccination cohorts. More generally, LIBRA-seq will be an integral tool for efficient and accurate B-cell
analysis, with the potential for broad impact on the fields of vaccine and antibody discovery not only for HIV-1
but also for a wide range of other pathogens of biomedical significance.
项目摘要。寻找有效的HIV-1疫苗仍然是当务之急,
了解免疫系统如何识别HIV-1有助于为疫苗设计提供信息。最近,很多
目前的研究重点是了解HIV-1感染和疫苗接种的抗体反应,
已经证明在治疗和预防中是有用的,并且作为抗体特异性疫苗设计的模板。而
针对HIV-1的抗体反应是多克隆和复杂的,下一代测序(NGS)的进展
技术使我们能够以前所未有的分辨率看到这种多克隆反应,作为一个集合,
单个单克隆抗体序列。序列鉴定之后通常是功能性抗体
表征,其主要组成部分是抗原/表位特异性的作图。
标准抗体分析流水线的主要挑战是序列鉴定和
抗体的功能表征过程通常是分离的。这样才能真正做到高...
抗体-抗原特异性的通量作图,仅提供了一小部分的有限信息,
从任何给定样品中选择抗体序列。为了应对这一挑战,我们建议制定一项
对于给定的样品,该技术将使得能够从抗体序列映射到抗原特异性,
单个高通量实验。该技术,LIBRA-seq(连接B细胞受体抗原特异性
通过测序),涉及将B细胞样品与(理论上无限的)
条形码化抗原,从而能够同时回收:(i)配对的重链-轻链BCR序列
和(ii)对给定B细胞的抗原特异性。特别是,该技术开发项目将广泛关注
有两个具体目标:在具体目标1中,我们将评估不同抗原条形码策略的效果,
其他测定变量对LIBRA-seq准确性和性能的影响。这一目标的目标是优化天秤座-
seq能够从测序实验中准确检测BCR序列和抗原特异性。在
具体目标2,我们的目标是同时定位给定HIV特异性B细胞的靶表位,
筛选具有表位敲除突变沿着野生型抗原的抗原混合物。这些
这些努力不仅将导致识别艾滋病毒特异性B细胞,而且还将提供残留水平
来自相同高通量实验的关于抗原上的特异性表位靶的信息。
最终,对于给定的感染或疫苗接种样本,LIBRA-seq技术将提供以下能力:
以在单个细胞中恢复数万至数十万B细胞的抗体序列和抗原特异性,
细胞水平。为了证明LIBRA-seq的实用性,我们将表征来自HIV-1感染的样品,
疫苗接种队列。更一般地说,LIBRA-seq将是高效和准确的B细胞免疫的不可或缺的工具。
分析,不仅对HIV-1的疫苗和抗体发现领域具有广泛影响的潜力,
而且还用于具有生物医学意义的广泛的其它病原体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ivelin Georgiev其他文献
Ivelin Georgiev的其他文献
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{{ truncateString('Ivelin Georgiev', 18)}}的其他基金
Technologies for High-Throughput Mapping of Antigen Specificity to B-Cell-Receptor Sequence
B 细胞受体序列抗原特异性高通量作图技术
- 批准号:
10734412 - 财政年份:2023
- 资助金额:
$ 85.71万 - 项目类别:
High-throughput mapping of antigen specificity to B-cell-receptor sequence for characterizing antibody responses in HIV-vaccinated and infected individuals
B 细胞受体序列抗原特异性的高通量图谱,用于表征 HIV 疫苗接种者和感染者的抗体反应
- 批准号:
10686168 - 财政年份:2020
- 资助金额:
$ 85.71万 - 项目类别:
Antibody repertoire characterization in the context of coronaviruses
冠状病毒背景下的抗体库表征
- 批准号:
10266227 - 财政年份:2020
- 资助金额:
$ 85.71万 - 项目类别:
High-throughput mapping of antigen specificity to B-cell-receptor sequence for characterizing antibody responses in HIV-vaccinated and infected individuals
B 细胞受体序列抗原特异性的高通量图谱,用于表征 HIV 疫苗接种者和感染者的抗体反应
- 批准号:
10252047 - 财政年份:2020
- 资助金额:
$ 85.71万 - 项目类别:
High-throughput mapping of antigen specificity to B-cell-receptor sequence for characterizing antibody responses in HIV-vaccinated and infected individuals
B 细胞受体序列抗原特异性的高通量图谱,用于表征 HIV 疫苗接种者和感染者的抗体反应
- 批准号:
10081501 - 财政年份:2020
- 资助金额:
$ 85.71万 - 项目类别:
Neutralization Fingerprinting Analysis of Polyclonal Antibody Responses against HIV-1
HIV-1 多克隆抗体反应的中和指纹图谱分析
- 批准号:
9407909 - 财政年份:2017
- 资助金额:
$ 85.71万 - 项目类别:
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